Efficacy of inotuzumab ozogamicin in patients with Philadelphia chromosome-positive relapsed/refractory acute lymphoblastic leukemia

Abstract

Background: Patients with relapsed/refractory (R/R) Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) have a poor prognosis and limited treatment options.

Methods: The efficacy of inotuzumab ozogamicin (InO), a humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, was evaluated in R/R ALL patients in the phase 1/2 study 1010 (NCT01363297) and open-label, randomized, phase 3 study 1022 (INO-VATE; NCT01564784). This analysis focused specifically on Ph+ R/R ALL patients. In study 1022, Ph+ patients were randomly assigned 1:1 to InO (n = 22) or standard intensive chemotherapy (SC) (n = 27) and 16 Ph+ patients in study 1010 received InO.

Results: In study 1022, rates of complete remission/complete remission with incomplete hematologic recovery (CR/CRi) and minimal residual disease (MRD) negativity (patients achieving CR/CRi) were higher with InO (CR/CRi = 73%; MRD = 81%) versus SC (CR/CRi = 56%; MRD = 33%). The corresponding rates in study 1010 were 56% (CR/CRi) and 100% (MRD). The hematopoietic stem cell transplantation (HSCT) rate in study 1022 was 41% versus 19% for InO versus SC; however, there was no benefit in overall survival (median OS: 8.7 vs 8.4 months; hazard ratio, 1.17 [95% CI, 0.64-2.14]). The probability of being event-free (progression-free survival) at 12 months was greater with InO versus SC (20.1% vs 4.8%).

Conclusion: Given the substantial improvement in responses and rates of HSCT, InO is an important treatment option for patients with R/R Ph+ ALL. Future studies need to consider better characterization of disease characteristics, more sensitive MRD measurements, MRD-directed therapy before HSCT, and potentially combination therapies, including tyrosine kinase inhibitors.

Keywords: Philadelphia chromosome; acute lymphoblastic leukemia; efficacy; hematopoietic stem cell transplantation; inotuzumab ozogamicin.

Conflict of interest statement

Wendy Stock has received research support and/or honoraria from AbbVie, Agios, the American Society of Hematology, Amgen, Astellas, Jazz, Kite, Pfizer, UpToDate, and Xencor and has served on advisory boards and/or as a consultant for Adaptive Biotechnologies, Agios, Astellas, Amgen, Daiichi‐Sankyo, Jazz, Kite, MorphoSys, Pfizer, and Servier. Giovanni Martinelli has served on speakers bureaus and/or as a consultant for ARIAD, Celgene, Pfizer, Roche, Bristol‐Myers Squibb, and Novartis. Matthias Stelljes has received research support from Pfizer, consulting honoraria from Pfizer, and personal fees from Amgen and Jazz. Daniel J. DeAngelo has received research support from AbbVie, Blueprint Pharmaceuticals, GlycoMimmetics, and Novartis and has received personal fees from Agios, Amgen, Autolos, Blueprint Pharmaceuticals, Forty‐Seven, Incyte, Jazz, Novartis, Pfizer, Servier, and Takeda. Nicola Gökbuget has received research support and/or honoraria from Amgen, Novartis, and Pfizer. Anjali S. Advani has received research support from AbbVie, Amgen, GlycoMimetics, and Macrogenics and honoraria from GlycoMimetics, KiTE Pharmaceuticals, Novartis, and Pfizer. Susan O’Brien has received research support from Acerta, Gilead, KiTE Pharmaceuticals, Pfizer, Pharmacyclics, Regeneron, Sunesis, and TG Therapeutics and honoraria from Alexion, Eisai, Gilead, Juno Therapeutics, Pfizer, Pharmacyclics, Sunesis, TG Therapeutics, and Verastem. Michaela Liedtke has received research support from Pfizer and personal fees from Amgen, Celgene, GlaxoSmithKline, Janssen, Oncopeptides, and Pfizer. Akil A. Merchant has received institutional support for clinical trials from Pfizer, has received research support from the National Institutes of Health and Pfizer, has received personal fees from Pfizer, and has served on the advisory board for Pfizer. Ryan D. Cassaday has received research funding from Amgen, Kite/Gilead, Merck, Pfizer, Vanda Pharmaceuticals, and Seattle Genetics, and has received personal fees from Amgen and Pfizer. Tao Wang is an employee of and owns stock in Pfizer. Hui Zhang is an employee of and owns stock in Pfizer. Erik Vandendries is an employee of and owns stock in Pfizer. Elias Jabbour has received research funding from AbbVie, Amgen, Bristol‐Myers Squibb, Pfizer, and Takeda; has received nonfinancial support from Adaptive Biotechnologies; has received personal fees from AbbVie, Adaptive Biotechnologies, Amgen, Astellas, Bristol‐Myers Squibb, Genentech, Pfizer, and Takeda. David I. Marks has served on the advisory board and as a consultant for Pfizer. Hagop M. Kantarjian has received research grants from AbbVie, Amgen, Ascentage, Bristol‐Myers Squibb, Daiichi‐Sankyo, Immunogen, Jazz, Novartis, Pfizer, and Sanofi; has received honoraria from AbbVie, Adaptive Biotechnologies, Amgen, Aptitude Health, BioAscend, Daiichi‐Sankyo, Delta Fly, Janssen Global, Novartis, Oxford Biomedical, Pfizer, and Takeda; and has served on the advisory board for Actinium.

© 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.

Figures

Figure 1

Patient population. Abbreviations: ALL, acute lymphoblastic leukemia; InO, inotuzumab ozogamicin; Ph+, Philadelphia chromosome–positive; R/R, relapsed/refractory; SC, standard chemotherapy.

Figure 2

Kaplan–Meier plot of overall survival among Philadelphia chromosome–positive patients with acute lymphoblastic leukemia in (A) study 1022 and (B) study 1010. Abbreviations: HR, hazard ratio; InO, inotuzumab ozogamicin; mOS, median overall survival; SC, standard chemotherapy.

Figure 3

Kaplan–Meier plot of progression‐free survival among Philadelphia chromosome–positive patients with acute lymphoblastic leukemia in (A) study 1022 and (B) study 1010. Abbreviations: HR, hazard ratio; InO, inotuzumab ozogamicin; mPFS, median progression‐free survival; SC, standard chemotherapy.